In order to obtain maximum tissue penetration, long wavelength absorbing photosensitizers have generated a great deal of interest as potential candidates for photodynamic therapy (PDT) (Dougherty, T. J. [1990] "Photodynamic Therapy For the Treatment of Cancer: Current Status and Advances", Photodynamic Therapy of Neoplastic Disease, pp. 1-20, CRC Press, Boca Raton, Fla.). Among such photosensitizers, a chlorin type benzoporphyrin derivative (BPD), a mixture of 21 and 22 as shown in FIG. 7, has been reported as a promising second generation photosensitizer for the treatment of cancer (Pandey, R. K.; Majchrzycki, D. F.; Dougherty, T. J.; and Smith, K. M., [1989] "Chemistry of Photofrin II and Some New Photosensitizers", Proc. SPIE, 1065, pp. 164-174). BPD is obtained as a mixture of isomers (ring "A" and ring "B" modified) by first reacting protoporphyrin IX dimethyl ester with dimethyl acetylenedicarboxylate; the Diels Alder adduct so obtained is then rearranged to the double-bond conjugated compound by treatment with 1,8-diaza bicyclo [5,4,0] undec 7 ene (DBU). The partially hydrolyzed monomethyl ester (as a mixture) of the ring "A" benzoporphyrin is claimed to be the most promising second generation PDT agent, and is currently in Phase I clinical trials (Richter, A. M.; Kelly, B.; Chow, J.; Liu, J. D.; Towers, G. H. N.; Levy, J.; and Dolphin, D., [1987] "Preliminary Studies on a More Effective phototoxic Agent Than Hematoporphyrin", J. Natl. Cancer Inst., 79, pp. 1327-1332).
Because photosensitizers for PDT are still not as effective as desired, there has been continuing effort to prepare more effective photosensitizers. Examples of such efforts are, for example, described in (a) Pandey, R. K.; Bellnier, D. A.; Smith, K. M.; Dougherty T. J. [1991] "Chlorin and Porphyrin Derivatives as potential photosensitizers in photodynamic Therapy", Photochem. Photobiol., 53, 65-72; (b) Bellnier, D. A.; Henderson, B. W.; Pandey, R. K.; Potter, W. R.; Dougherty, T. J., [1993] "Murine Pharmacokinetics and Antitumor Efficacy of the Photodynamic Sensitizer 2-(1-hexyloxyethyl)-2-devinylpyropheophorbide-a (HPPH), J. Photochem. Photobiol., 20, 55-61; (c) Pandy, R. K.; Shiau, F.-Y.; Sumlin, A. B.; Dougherty, T. J.; Smith, K. M., [1992] "Structure/Activity Relationships Among Photo-Sensitizers Related to Pheophorbides and Bacteriopheophorbides", Bioorg. Med. Chem. Lett., 2, 491-496; (d) Meunier, I.; Pandey, R. K. p Walker, M. M.; Senge, M. O.; Dougherty, T. J.; Smith, K. M., [1992] "New Syntheses of Benzoporphyrin Derivatives and Analogues for Use in Photodynamic Therapy", Bioorg. Med. Chem. Lett., 2, 1575-1580; and (e) Evenson, J. F.; Sommer, S.; Rimington, C.; Moan, J., 1987] "Photodynamic Therapy of CH3 Mouse Mammary Carcinoma with Hematoporphyrin Diethers as Sensitizers", Br. J. Cancer, 55, 483-486.
Recently, an alternate route for the preparation of BPDs has been reported and showed that treatment of the initial unconjugated Diels Alder adduct with triethylamine gives the trans isomer, which upon subsequent treatment with DBU produces the cis isomer (red shifted by 6 nm) in modest yield (Meunier, I.; Pandey, R. K.; Walker, M. M.; Senge, M. O.; Dougherty, T. J.; and Smith, K. M., [1992] "New Syntheses of Benzoporphyrin Derivatives and Analogues for Use in Photodynamic Therapy", Bioorg. Med Chem. Lett., 2, pp. 1575-1580). The cis- isomer, as a mixture of 20 and 28,can also be obtained by reacting the initial unconjugated Diels Alder adduct from protoporphyrin IX dimethyl ester 3 directly with DBU. Among BPDs tested so far, the biological activity of only the cis- isomers [ring "A" modified, (21, 22)] and [ring "B" modified, (29, 30 shown in FIG. 8)] of BPD (as a mixture of two monomethyl esters) have been reported. Richter et al. supra have shown that the BPD in which ring "A" is modified is more active than ring "B" modified isomer.